The overall goals of this proposal are to understand the role of alpha- synuclein in the pathogenesis and pathology of Parkinson's disease (PD) and to define the molecular mechanisms of dopaminergic neuronal injury in animal models of PD. The program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complementary areas of expertise who have long been committed to the studies of neurodegenerative diseases. Their aim will be to integrate the activities of various disciplines than if each project were pursued individually. The program has two themes. First, the biology and pathobiology of alpha- synuclein, implicated in familial PD, will be defined in human brain from PD with and without cognitive impairment and age matched controls. This will be complemented by studying the cell biology of alpha-synuclein in in vivo and in vitro model systems. Transgenic animal models of familial PD will be produced by generating animals over-expressing the A53T and A30P mutations of alpha-synuclein. Second, molecular, transgenic, neuropathologic, cell biologic and neurobehavioral approaches are proposed to examine the mechanism of neuronal injury and neuroprotection in the MPTP model of PD. We will determine the neurotoxic mechanisms associated with nitric oxide signaling and superoxide anion formation and scavenging and the role of poly (ADP ribose) polymerase and potential derangements in the biology of alpha-synuclein in response to MPTP. Also, identification of differentially expressed genes following the MPTP neurotoxicity paradigm will be characterized in the striatum and substantia nigra dopamine containing cells. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning mechanisms of neuronal injury and neuroprotection in animal models of Parkinson's Disease and to lead to better understanding of the function and the role of alpha-synuclein in normal and pathophysiologic processes related to PD. The program consists of four projects: 1) Cognitive Impairment in Parkinson's Disease: The Role of alpha-Synuclein 2) Molecular Mechanism's of MPTP Neurotoxicity; 3) alpha-Synuclein and Interacting Proteins: In Vitro Studies; 4) Biology of alpha-Synuclein in Mouse Models of PD; and is supported by four core facilities: A) Administration and Training; B) Transgenic and Neurobehavior; c) Neuropathology and D) Clinical.